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Circulatory disease mortality in the Massachusetts tuberculosis fluoroscopy cohort study

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Abstract

High-dose ionizing radiation is associated with circulatory disease. Risks from lower-dose fractionated exposures, such as from diagnostic radiation procedures, remain unclear. In this study we aimed to ascertain the relationship between fractionated low-to-medium dose radiation exposure and circulatory disease mortality in a cohort of 13,568 tuberculosis patients in Massachusetts, some with fluoroscopy screenings, between 1916 and 1961 and follow-up until the end of 2002. Analysis of mortality was in relation to cumulative thyroid (cerebrovascular) or lung (all other circulatory disease) radiation dose via Poisson regression. Over the full dose range, there was no overall radiation-related excess risk of death from circulatory disease (n = 3221; excess relative risk/Gy −0.023; 95 % CI −0.067, 0.028; p = 0.3574). Risk was somewhat elevated in hypertensive heart disease (n = 89; excess relative risk/Gy 0.357; 95 % CI −0.043, 1.030, p = 0.0907) and slightly decreased in ischemic heart disease (n = 1950; excess relative risk/Gy −0.077; 95 % CI −0.130, −0.012; p = 0.0211). However, under 0.5 Gy, there was a borderline significant increasing trend for all circulatory disease (excess relative risk/Gy 0.345; 95 % CI −0.032, 0.764; p = 0.0743) and for ischemic heart disease (excess relative risk/Gy 0.465; 95 % CI, −0.032, 1.034, p = 0.0682). Pneumolobectomy increased radiation–associated risk (excess relative risk/Gy 0.252; 95 % CI 0.024, 0.579). Fractionation of dose did not modify excess risk. In summary, we found no evidence of radiation-associated excess circulatory death risk overall, but there are indications of excess circulatory death risk at lower doses (<0.5 Gy). Although consistent with other radiation-exposed groups, the indications of higher risk at lower doses are unusual and should be confirmed against other data.

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References

  1. United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR). UNSCEAR 2006 Report. Annex A. Epidemiological Studies of Radiation and Cancer. New York: United Nations; 2008. p. 13–322.

  2. Committee to Assess Health Risks from Exposure to Low Levels of Ionizing Radiation NRC. Health Risks from Exposure to Low Levels of Ionizing Radiation: BEIR VII—Phase 2. Washington, DC: National Academy Press; 2006. p. 1-406.

  3. Little MP, Kleinerman RA, Stovall M, Smith SA, Mabuchi K. Analysis of dose response for circulatory disease after radiotherapy for benign disease. Int J Radiat Oncol Biol Phys. 2012;84(5):1101–9. doi:10.1016/j.ijrobp.2012.01.053.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Darby SC, Ewertz M, McGale P, et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med. 2013;368(11):987–98. doi:10.1056/NEJMoa1209825.

    Article  CAS  PubMed  Google Scholar 

  5. Mulrooney DA, Yeazel MW, Kawashima T, et al. Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort. BMJ. 2009;339:b4606.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Tukenova M, Guibout C, Oberlin O, et al. Role of cancer treatment in long-term overall and cardiovascular mortality after childhood cancer. J Clin Oncol. 2010;28(8):1308–15. doi:10.1200/JCO.2008.20.2267.

    Article  PubMed  Google Scholar 

  7. Shimizu Y, Kodama K, Nishi N, et al. Radiation exposure and circulatory disease risk: Hiroshima and Nagasaki atomic bomb survivor data, 1950–2003. BMJ. 2010;340:b5349.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Little MP, Azizova TV, Bazyka D, et al. Systematic review and meta-analysis of circulatory disease from exposure to low-level ionizing radiation and estimates of potential population mortality risks. Environ Health Perspect. 2012;120(11):1503–11. doi:10.1289/ehp.1204982.

    Article  PubMed  PubMed Central  Google Scholar 

  9. McMillan TJ, Bennett MR, Bridges BA, et al. Circulatory disease risk. Report of the independent Advisory Group on Ionising Radiation. Health Protection Agency, Holborn Gate, 330 High Holborn, London; 2010. p. 1–116.

  10. Boice JD Jr, Preston D, Davis FG, Monson RR. Frequent chest X-ray fluoroscopy and breast cancer incidence among tuberculosis patients in Massachusetts. Radiat Res. 1991;125(2):214–22.

    Article  PubMed  Google Scholar 

  11. Howe GR. Lung cancer mortality between 1950 and 1987 after exposure to fractionated moderate-dose-rate ionizing radiation in the Canadian fluoroscopy cohort study and a comparison with lung cancer mortality in the atomic bomb survivors study. Radiat Res. 1995;142(3):295–304.

    Article  CAS  PubMed  Google Scholar 

  12. Howe GR, McLaughlin J. Breast cancer mortality between 1950 and 1987 after exposure to fractionated moderate-dose-rate ionizing radiation in the Canadian fluoroscopy cohort study and a comparison with breast cancer mortality in the atomic bomb survivors study. Radiat Res. 1996;145(6):694–707.

    Article  CAS  PubMed  Google Scholar 

  13. Little MP, Boice JD Jr. Comparison of breast cancer incidence in the Massachusetts tuberculosis fluoroscopy cohort and in the Japanese atomic bomb survivors. Radiat Res. 1999;151(2):218–24.

    Article  CAS  PubMed  Google Scholar 

  14. Davis FG, Boice JD Jr, Hrubec Z, Monson RR. Cancer mortality in a radiation-exposed cohort of Massachusetts tuberculosis patients. Cancer Res. 1989;49(21):6130–6.

    CAS  PubMed  Google Scholar 

  15. Zablotska LB, Little MP, Cornett RJ. Potential increased risk of ischemic heart disease mortality with significant dose fractionation in the Canadian fluoroscopy cohort study. Am J Epidemiol. 2014;179(1):120–31. doi:10.1093/aje/kwt244.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Boice JD Jr. Follow-up methods to trace women treated for pulmonary tuberculosis, 1930–1954. Am J Epidemiol. 1978;107(2):127–39.

    PubMed  Google Scholar 

  17. Boice JD Jr, Rosenstein M, Trout ED. Estimation of breast doses and breast cancer risk associated with repeated fluoroscopic chest examinations of women with tuberculosis. Radiat Res. 1978;73(2):373–90.

    Article  PubMed  Google Scholar 

  18. Boice JD, Monson RR, Rosenstein M. Cancer mortality in women after repeated fluoroscopic examinations of the chest. J Natl Cancer Inst 1981;66(5):863–7.

  19. Ridker PM. Inflammation, infection, and cardiovascular risk: how good is the clinical evidence? Circulation. 1998;97(17):1671–4.

    Article  CAS  PubMed  Google Scholar 

  20. Gura T. Infections: a cause of artery-clogging plaques? Science 1998;281(5373):35–7.

  21. McCullagh P, Nelder JA. Generalized linear models. 2nd edition. Monographs on statistics and applied probability 37. Boca Raton, FL: Chapman and Hall/CRC; 1989. p. 1–526.

  22. Preston DL, Lubin JH, Pierce DA, McConney ME. Epicure release 2.10. Seattle: Hirosoft International; 1998.

  23. Austin PC, Tu JV. Automated variable selection methods for logistic regression produced unstable models for predicting acute myocardial infarction mortality. J Clin Epidemiol. 2004;57(11):1138–46. doi:10.1016/j.jclinepi.2004.04.003.

    Article  PubMed  Google Scholar 

  24. Akaike H. Information theory and an extension of the maximum likelihood principle. In: Petrov BN, Czáki F, editors. 2nd International symposium on information theory. Budapest: Akadémiai Kiadó; 1973. p. 267–81.

    Google Scholar 

  25. Akaike H. Likelihood of a model and information criteria. J Econ. 1981;16(1):3–14.

    Article  Google Scholar 

  26. R Project. R version 3.1.1 http://www.r-project.org/. 2014.

  27. Hastie T, Tibshirani R. Generalized additive models for medical research. Stat Methods Med Res. 1995;4(3):187–96.

    Article  CAS  PubMed  Google Scholar 

  28. Little MP, Tawn EJ, Tzoulaki I, et al. A systematic review of epidemiological associations between low and moderate doses of ionizing radiation and late cardiovascular effects, and their possible mechanisms. Radiat Res. 2008;169(1):99–109. doi:10.1667/RR1070.1.

    Article  CAS  PubMed  Google Scholar 

  29. Schultz-Hector S, Trott KR. Radiation-induced cardiovascular diseases: is the epidemiologic evidence compatible with the radiobiologic data? Int J Radiat Oncol Biol Phys. 2007;67(1):10–8. doi:10.1016/j.ijrobp.2006.08.071.

    Article  CAS  PubMed  Google Scholar 

  30. Mitchel REJ, Hasu M, Bugden M, et al. Low-dose radiation exposure and atherosclerosis in ApoE −/− mice. Radiat Res. 2011;175(5):665–76. doi:10.1667/RR2176.1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Adams MJ, Grant EJ, Kodama K, et al. Radiation dose associated with renal failure mortality: a potential pathway to partially explain increased cardiovascular disease mortality observed after whole-body irradiation. Radiat Res. 2012;177(2):220–8. doi:10.1667/RR2746.1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lenarczyk M, Lam V, Jensen E, et al. Cardiac injury after 10 Gy total body irradiation: indirect role of effects on abdominal organs. Radiat Res. 2013;180(3):247–58. doi:10.1667/RR3292.1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Rosenstein M. Personal communication to Mark Little. 2014.

  34. Kusunoki Y, Kyoizumi S, Hirai Y, et al. Flow cytometry measurements of subsets of T, B and NK cells in peripheral blood lymphocytes of atomic bomb survivors. Radiat Res. 1998;150(2):227–36.

    Article  CAS  PubMed  Google Scholar 

  35. Danesh J, Whincup P, Lewington S, et al. Chlamydia pneumoniae IgA titres and coronary heart disease. Prospective study and meta-analysis. Eur Heart J. 2002;23(5):371–5. doi:10.1053/euhj.2001.2801.

    Article  CAS  PubMed  Google Scholar 

  36. Whincup P, Danesh J, Walker M, et al. Prospective study of potentially virulent strains of Helicobacter pylori and coronary heart disease in middle-aged men. Circulation. 2000;101(14):1647–52.

    Article  CAS  PubMed  Google Scholar 

  37. Grayston JT, Kronmal RA, Jackson LA, et al. Azithromycin for the secondary prevention of coronary events. N Engl J Med. 2005;352(16):1637–45. doi:10.1056/NEJMoa043526.

    Article  CAS  PubMed  Google Scholar 

  38. Cannon CP, Braunwald E, McCabe CH, et al. Antibiotic treatment of Chlamydia pneumoniae after acute coronary syndrome. N Engl J Med. 2005;352(16):1646–54. doi:10.1056/NEJMoa043528.

    Article  CAS  PubMed  Google Scholar 

  39. Lowe D, Raj K. Premature aging induced by radiation exhibits pro-atherosclerotic effects mediated by epigenetic activation of CD44 expression. Aging Cell. 2014;13(5):900–10. doi:10.1111/acel.12253.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Little MP, Gola A, Tzoulaki I. A model of cardiovascular disease giving a plausible mechanism for the effect of fractionated low-dose ionizing radiation exposure. PLoS Comput Biol. 2009;5(10):e1000539. doi:10.1371/journal.pcbi.1000539.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Fuster V, Moreno PR, Fayad ZA, Corti R, Badimon JJ. Atherothrombosis and high-risk plaque: part I: evolving concepts. J Am Coll Cardiol. 2005;46(6):937–54. doi:10.1016/j.jacc.2005.03.074.

    Article  PubMed  Google Scholar 

  42. Virmani R, Burke AP, Farb A, Kolodgie FD. Pathology of the vulnerable plaque. J Am Coll Cardiol. 2006;47(8 Suppl):C13–8. doi:10.1016/j.jacc.2005.10.065.

    Article  CAS  PubMed  Google Scholar 

  43. Little MP, Tawn EJ, Tzoulaki I, et al. Review and meta-analysis of epidemiological associations between low/moderate doses of ionizing radiation and circulatory disease risks, and their possible mechanisms. Radiat Environ Biophys. 2010;49(2):139–53. doi:10.1007/s00411-009-0250-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Little MP, Zablotska LB, Lipshultz SE. Ischemic heart disease after breast cancer radiotherapy. N Eng J Med. 2013;368(26):2523–4. doi:10.1056/NEJMc1304601#SA1.

    Article  CAS  Google Scholar 

  45. Burns DM. Epidemiology of smoking-induced cardiovascular disease. Prog Cardiovasc Dis. 2003;46(1):11–29. doi:10.1016/S0033-0620(03)00079-3.

    Article  PubMed  Google Scholar 

  46. Wilson PW, D’Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation. 1998;97(18):1837–47.

    Article  CAS  PubMed  Google Scholar 

  47. Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004;364(9438):937–52. doi:10.1016/S0140-6736(04)17018-9.

    Article  PubMed  Google Scholar 

  48. Yamada M, Wong FL, Fujiwara S, Akahoshi M, Suzuki G. Noncancer disease incidence in atomic bomb survivors, 1958–1998. Radiat Res. 2004;161(6):622–32. doi:10.1667/RR3183

    Article  CAS  PubMed  Google Scholar 

  49. Azizova TV, Muirhead CR, Druzhinina MB, et al. Cardiovascular diseases in the cohort of workers first employed at Mayak PA in 1948–1958. Radiat Res. 2010;174(2):155–68. doi:10.1667/RR1789.1.

    Article  CAS  PubMed  Google Scholar 

  50. Azizova TV, Haylock RGE, Moseeva MB, Bannikova MV, Grigoryeva ES. Cerebrovascular diseases incidence and mortality in an extended Mayak Worker Cohort 1948–1982. Radiat Res. 2014;182(5):529–44. doi:10.1667/RR13680.1.

    Article  CAS  PubMed  Google Scholar 

  51. International Commission on Radiological Protection. ICRP statement on tissue reactions and early and late effects of radiation in normal tissues and organs - threshold doses for tissue reactions in a radiation protection context. ICRP publication 118. Ann. ICRP. 2012;41(1–2):1–322. doi:10.1016/j.icrp.2007.10.003.

    Google Scholar 

  52. Schöllnberger H, Kaiser JC, Jacob P, Walsh L. Dose-responses from multi-model inference for the non-cancer disease mortality of atomic bomb survivors. Radiat Environ Biophys. 2012;51(2):165–78. doi:10.1007/s00411-012-0410-4.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Little MP, Azizova TV, Bazyka D, et al. Comment on “Dose-responses from multi-model inference for the non-cancer disease mortality of atomic bomb survivors” (Radiat. Environ. Biophys (2012) 51:165–178) by Schöllnberger et al. Radiat Environ Biophys 2013;52(1):157–9. doi:10.1007/s00411-012-0453-6.

  54. McGeoghegan D, Binks K, Gillies M, Jones S, Whaley S. The non-cancer mortality experience of male workers at British Nuclear Fuels plc, 1946-2005. Int J Epidemiol. 2008;37(3):506–18. doi:10.1093/ije/dyn018.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Muirhead CR, O’Hagan JA, Haylock RGE, et al. Mortality and cancer incidence following occupational radiation exposure: third analysis of the National Registry for Radiation Workers. Br J Cancer. 2009;100(1):206–12. doi:10.1038/sj.bjc.6604825.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Vrijheid M, Cardis E, Ashmore P, et al. Mortality from diseases other than cancer following low doses of ionizing radiation: results from the 15-Country Study of nuclear industry workers. Int J Epidemiol. 2007;36(5):1126–35. doi:10.1093/ije/dym138.

    Article  CAS  PubMed  Google Scholar 

  57. Krestinina LY, Epifanova S, Silkin S, et al. Chronic low-dose exposure in the Techa River Cohort: risk of mortality from circulatory diseases. Radiat Environ Biophys. 2013;52(1):47–57. doi:10.1007/s00411-012-0438-5.

    Article  PubMed  Google Scholar 

  58. Grosche B, Lackland DT, Land CE, et al. Mortality from cardiovascular diseases in the Semipalatinsk historical cohort, 1960–1999, and its relationship to radiation exposure. Radiat Res. 2011;176(5):660–9. doi:10.1667/RR2211.1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

MPL and AVB were supported by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute (NCI), Division of Cancer Epidemiology and Genetics, and LBZ by NCI grants 5K07CA132918 and 1R03CA188614. The authors are grateful for the detailed and helpful comments of Dr Marvin Rosenstein and a referee.

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Authors and Affiliations

  1. Radiation Epidemiology Branch, National Cancer Institute, Bethesda, MD, 20892-9778, USA

    Mark P. Little & Alina V. Brenner

  2. National Cancer Institute, Room 7E546, 9609 Medical Center Drive, MSC 9778, Rockville, MD, 20892-9778, USA

    Mark P. Little

  3. Department of Epidemiology and Biostatistics, School of Medicine, University of California San Francisco, San Francisco, CA, 94118, USA

    Lydia B. Zablotska

  4. Department of Pediatrics, Wayne State University School of Medicine and Children’s Hospital of Michigan, Detroit, MI, 48201-2196, USA

    Steven E. Lipshultz

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Appendices

Appendix 1: Background models selected

See Tables 8, 9, 10, 11, 12, 13 and 14.

Table 8 Analysis of deviance of all circulatory disease mortality
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Table 9 Analysis of deviance of all cerebrovascular disease mortality
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Table 10 Analysis of deviance of all heart disease mortality
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Table 11 Analysis of deviance of ischemic heart disease mortality
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Table 12 Analysis of deviance of non-ischemic heart disease mortality
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Table 13 Analysis of deviance of hypertensive heart disease mortality
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Table 14 Analysis of deviance of all circulatory disease mortality apart from heart disease and cerebrovascular disease
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Appendix 2: Effect of alternative background models selected via minimizing Akaike information criterion

In this appendix we consider an alternative set of explanatory background models for each endpoint, selected via an automatic variable selection process, by minimizing the Akaike information criterion (AIC) [24, 25]. Minimizing AIC is a standard method of variable selection that avoids over-parameterised (and therefore over-fitted) models. AIC penalizes against overfitting by adding 2 × [number of fitted parameters] to the model deviance. We used an iterative mixed-forward–backward stepwise procedure to minimize AIC using models with Poisson error via R [26].

The models used the set of candidate variables listed in Table 15, in which the optimal models chosen are also indicated. We provide the analog of Table 2 using these alternative background models in Table 16.

Table 15 Candidate variables for fits to various circulatory disease mortality endpoints in analysis using minimization of AIC to select the background model
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Table 16 Excess relative risks for circulatory disease mortality in the Massachusetts tuberculosis fluoroscopy cohort and modification by age at entry, years since entry, and dose rate, using alternative optimal models selected to minimize AIC as in Table 15
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Appendix 3: Generalized additive models (GAM)

See Table 17.

Table 17 GAM fitted to circulatory disease mortality in the Massachusetts tuberculosis fluoroscopy cohort
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Little, M.P., Zablotska, L.B., Brenner, A.V. et al. Circulatory disease mortality in the Massachusetts tuberculosis fluoroscopy cohort study. Eur J Epidemiol 31, 287–309 (2016). https://doi.org/10.1007/s10654-015-0075-9

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